Field of the Invention
The present invention relates to a bilirubin excretion enhancer. More specifically, the present invention relates to a bilirubin excretion enhancer with a serum albumin domain II-like protein, containing the subdomain IIA of serum albumin, as an active ingredient.
Description of Related Art
Bilirubin is a final product of the degradation of a heme which is a component of a red blood cell. Within various isomers thereof, the isomer that exists most abundantly in the body is 4Z, 15Z-bilirubin-IXα (hereinafter, referred to as 4Z, 15Z-BR). A newborn is susceptible to hyperbilirubinemia and jaundice because of the immaturity of liver, which is a 4Z, 15Z-BR metabolizing tissue. If the level of bilirubin becomes high, bilirubin may deposit on cranial nerves, thereby causing encephalopathy. Nowadays, the first-line therapy for jaundice of the newborn is phototherapy. Phototherapy is a therapy in which the skin of a newborn is irradiated with light to convert 4Z, 15Z-BR having a low water solubility to an isomer having a high water solubility such as 4Z, 15E-bilirubin-IXα (4Z, 15E-BR) or Z-lumirubin, and promote the excretion of bilirubin into urine and bile. The mechanism for bilirubin phototherapy is shown in FIG. 1. However, although phototherapy is effective for bilirubin deposited on the skin, it is not effective for bilirubin in blood because light does not reach bilirubin in blood. Moreover, since the skin of an adult hardly transmits light, phototherapy is performed only on a newborn.
Therefore, at this time, plasma exchange in which plasma in blood is exchanged to lower the bilirubin concentration or adsorption removal of bilirubin using a column for bilirubin adsorption is performed. However, the adsorption removal method involves an increased risk of infectious diseases, and removes proteins and vitamins useful for a living body.
Human serum albumin (hereinafter, referred to as HSA) is the main protein present in adult serum, is produced in the liver, and functions as a carrier transporting various serum molecules. Moreover, bilirubin binds to HSA and is carried to the liver, and then binds to glucuronic acid in the liver to become a conjugated bilirubin that dissolves in water more easily. This conjugated bilirubin is secreted from the liver as bile.
HSA is a single-stranded protein (SEQ ID NO: 10) of 585 amino acids, and the basic structure is composed of three domains (domain I, II and III) having a high homology, each of which is segmented into subdomains (A and B). The domain I ranges amino acid positions 1 to 197, the domain II ranges amino acid positions 187 to 385, and the domain III ranges amino acid positions 381 to 585.
It is reported that the site I (domain II) is a high affinity binding site for bilirubin. The inventors have obtained an albumin variant having a high binding activity with respect to bilirubin, and found that the amino acids at positions 195 and 199 contribute to bilirubin binding (Patent Document 1). Moreover, the inventors have produced a protein including the domain I of HSA by genetic recombination (Patent Document 2).